Process for preparing 5-fluoronicotinic acid



ilnitcd States atent 3,027,380 Patented Mar. 27, 1952 3,027,380 PROCESS FOR PREPARING S-FLUORO- NICOTFNIC ACID Nelson J. Leonard, Urbana, UL, and Lynn R. Peters, In-

dianapolis, ind, assignors to li Lilly and Company,

Indianapolis, Ind, a corporation of Indiana No Drawing. Filed June 10, 1959, Ser. No. 819,228

3 Claims. (Cl. 260-2955) This invention relates to a novel synthesis of S-fluoronicotinic acid and to a novel intermediate useful in the synthesis.

Heretofore 5-fiuoronicotinic acid has been synthesized by a process which involved expensive starting materials and many reaction steps, some of them hazardous. Attempts to prepare S-fluoronicotinic acid by methods useful for the synthesis of the closely related compound, 5- bromonicotinic acid, have yielded only compounds from which the fluorine had been eliminated by the reaction conditions. For example, Hawkins and Roe, Journal of Organic Chemistry, vol. 14, p. 328 (1949), stated that oxidation of 3-fluoroquinoline with nitric acid, neutral permanganate or acid permanganate failed to yield the desired 5-fiuoronicotinic acid, and that only fluorine-free materials were recovered.

By this invention there is provided a novel method of synthesizing 5-fluoronicotinic acid, said method comprising oxidizing 3-fluor0quinoline to S-fluoroquinolinic acid, and subsequently decarboxylating the S-fluoroquinolinic acid to yield 5-fluoronicotinic acid.

The process of this invention is illustrated by the following equation:

F- r coon Heat coon -GOOH The oxidation of 3-fiuoroquinoline to S-fiuoroquinolinic acid employs oxidizing agents which yield nascent or atomic oxygen. Such agents include, for example, hydrogen peroxide associated with a heavy metal salt, and anodic oxygen such as can be provided by electrolysis.

When the oxidation is carried out with hydrogen peroxide the metal salt to be employed in conjunction with the peroxide is a water-soluble salt of one of the transition elements, for example, a salt of copper. The metal salt preferably is present in an amount which is at least a stoichiometric amount with respect to the 3-fiuoroquinoline.

In a preferred embodiment of our novel oxidation step, hydrogen peroxide and an equimolar amount of copper acetate are employed since the oxidation product, fiuoroquinolinic acid, precipitates from solution in the form of its copper salt, and so can be readily isolated. The copper salt is converted to the free S-fluoroquinolinic acid by conventional means, as by treatment of a solution containing it with'hydrogen sulfide.

The hydrogen peroxide-copper acetate oxidizing agent preferably is used with a solvent such as a lower saturated aliphatic carboxylic acid or a halogenated aliphatic acid, for example, acetic or trifluoro acetic acid.

The oxidation is preferably carried out at a temperature of about 65 0, although the process is operative over a temperature range from about room temperature to about 80 C.

When the source of nascent oxygen used to transform 3-iluoroquinoline to S-fluoroquinolinic acid is anodic oxygen, a standard electrolytic oxidation apparatus can be employed. Concentrated sulfuric acid is preferred as the electrolyte, and a lead anode and noble metal cathode are conveniently used. The temperature of oxidation can be the same with anodic oxidation as when hydrogen peroxide is the source of nascent oxygen.

5 -fluoroquinolinic acid, the novel intermediate furnished by this invention, is a white crystalline solid which melts at about 147 C.

Since the S-fluoroquinolinic acid is customarily present in acidic solution after the oxidation, it exists in such solution as an acid addition salt. The compound is readily isolated from the acid solution by adjusting the pH of the solution to about pH=2.5 with a base such as sodium hydroxide or ammonium hydroxide, whereupon a cationic salt, e.g., the monosodium or monoammonium salt, respectively, of S-fluoroquinoiinic acid precipitates. The free acid can be prepared from the cationic salt by carefully neutralizing an ethanolic dispersion of the salt with a stoichiometric amount of ethanolic hydrogen chloride. The solution is filtered to remove the precipitated salt and the filtrate is evaporated to yield the S-fiuoroquinolinic acid. If desired, the acid can be purified by recrystallizing it from hot acetone.

Moderately water-soluble monocationic salts of 5- fluoroquinolinic acid are useful in the isolation and purification of the compound. Among the useful monocationic salts of S-fiuoroquinolinic acid are the sodium, potassium, ammonium, tetramethylammonium, and like salts. Such salts can readily be prepared by suspending the acid in water and adjusting the mixture to about pH 2.5 by treating it with an equivalent of the alkaline agent.

The second step of our novel process, the decarboxylation of S-fiuoroquinolinic acid, is carried out by heating the quinolinic acid either alone or in a solvent. In the event the S-fiuoroquinolinic acid is heated alone, the heating can be carried out in vacuo so that the S-fiuoronicotinic acid formed upon decarboxylation will sublime and will be carried out of the reaction zone. For example, sublimation of S-fluoroquinolinic acid at a temperature in the range of about l50-220 C. and a pressure below about 10 mm. of mercury results in the production of S-fiuoronicotinic acid.

In the event S-fiuoroquinolinic acid is decarboxylated to S-fiuoronicotinic acid by heating it in a solvent, the solvent selected should be a polar solvent having a boiling point upwards of about 150 C., for example, cyclohexanol, nitrobenzene or acetic acid. The S-fiuoronicotinic acid can be recovered from the solvent by an extractive procedure, as by extraction with aqueous alkali. The pH of the extract is adjusted to about pH 2.5 with acid, and the mixture is cooled to cause precipitation of the S-fiuoronicotinic acid.

This invention is further illustrated by the following specific examples:

EXAMPLE 1 Preparation of 5-Flu0r0quinolinic Acid 120 g. of cupric acetate were dissolved in 1500 ml. of Water in a round bottom flask equipped with agitator, thermometer, and dropping funnel. A second solution of 58.8 g. of 3-fluoroquinoline in g. of glacial acetic acid was added slowly and with vigorous stirring to the above solution. After the addition was complete, the mixture was heated to about 65 C. and 560 g. of 30 percent hydrogen peroxide were slowly added. After the addition of the hydrogen peroxide was complete, the temperature of the reaction mixture was held at about 65 C. for six hours during which time evolution of gas ceased. The reaction mixture was cooled and a pale blue solid precipitate comprising copper S-fiuoroquinolinate dihydrate was separated by filtration. The precipitate was Washed with cold water and was dried in vacuo at a temperature of about 40-50 C. I

The dry precipitate was dispersed in 150 ml. of a 10 percent hydrochloric acid solution. Hydrogen sulfide gas was passed through the reaction mixture until the pale blue solid had disappeared. The reaction mixture was filtered, thus removing the insoluble copper sulfide formed in the above reaction. The filtrate was concentrated in vacuo to a volume of about 100 mls. The concentrate containing S-fiuoroquinolinic acid was decolorized' by treatment with activated carbon. After removal of the carbon, sufiicient 5 N sodium hydroxide solution was added to the acidic filtrate to bring it to about pH 2.5. Thefiltrate was cooled to about C. and allowed to stand several hours. The monosodium salt of -fluoroquinolinic acid which crystallized out was collected by filtration. About 40 g. of the monosodiurn salt of S-fiuoroquinolinic acid were obtained. The monosodium salt was purified by recrystallization from hot water.

AnaIysis.-Calculated: N, 6.76. Found: N, 6.54. M01. wt. calculated: 207. M01. wt. found: 204. (By electrometric titration in water, pKa at 4.2 and 7.5.)

20.7 g. of the monosodium salt of S-fiuoroquinolinic acid was suspended in anhydrous ethanol. The solution was neutralized with 100 ml. of l N ethanolic hydrogen chloride. The sodium chloride produced by the reaction was separated by filtration and the filtrate was evaporated to dryness yielding crystalline S-fluoroquinolinic acid which melted at about 147 C. after recrystallization from acetone.

Analysis.Calculated: N, 7.56. Found: N, 7.67.

One gram of S-fluoroquinolinic acid was sublimed in vacuo at a temperature of about 170 C. and a pressure of about 7 mm. of mercury. 0.7 g. of sublimed S-fiuoronicotinic acid were obtained, melting at about 189,192 C. The sublimate was recrystallized from hot water to yield 5-fiuoronicotinic acid of more compact crystal structure.

EXAMPLE 2 Preparation of 5-Flu0r0quin0linic Acid A cell was prepared consisting of a glass vessel 3 inches in height and 2 /2 inches in diameter containing a fine porosity alundum cup 19 mm. in diameter surrounded by a cylindrical lead sheet anode of 7 inches in circumference and 1 inch in height. The cup contained an 18 gauge platinum wire cathode. The lead anode was activated by alternating the polarity of the cell during six to ten minute intervals at a current of 0.5 amps. using a 20 percent sulfuric acid electrolyte.

In the activation process the lead anode was coated with lead oxide and then the coating was reduced to spongy lead by reversing the polarity of the cell. The anode compartment was emptied and was then charged with a mixture of 17.1 g. of 3-fluoroquinoline, 60 g. of 36 N sulfuric acid, 0.01 g. of vanadium pentoxide catalyst and sufiicient water to bring the volume to about 120 ml. The cell was heated to about 65-70 C. and was maintained in this temperature range throughout the oxidation. The oxidation was carried out by passing a current of 2.3 amps. through the cell for 5 hours, followed by a period of 46 hours during which 0.7 amp. current was passed through the cell and by a period of about 75 hours during which time a current of about 0.35 amp. was passed through the cell. The oxidation was continued until the dark red color had disappeared from the mixture. During the oxidation the sulfuric acid level in the cathode cup was maintained slightly higher than the level of the solution surrounding the anode by the gradual addition of 18 N sulfuric acid.

After the termination of the oxidation, the solution containing S-fluoroquinolinic acid sulfate was filtered and S-fiuoroquinolinic acid produced during the oxidation was precipitated as the monoammonium salt byraising the pH of the solution to about 1.7 with 28 percent ammonium hydroxide while cooling the oxidation mixture to about 12 C. The ammonium S-fiuoroquinolinate salt was separated by filtration, and the filter cake was washed with cold water. S-fluoroquinolinic acid was obtained from the ammonium salt by the method used in Example 1 for the preparation of the free acid from the monosodium salt.

A second amount of S-fluoroquinolinic acid crystals was obtained as follows: The pH of the acidic filtrate was raised to about 3 and an excess of a saturated copper sulfate solution was added thereto. The mixture was warmed at about C. on a steam bath for one hour, thus forming the insoluble copper salt of S-fiuOroquinolinic acid. Free S-fluoroquinolinic acid was obtained from the copper salt by the hydrogen sulfide process described in Example 1.

EXAMPLE 3 Pfieparation of S-Fiuoronicotinic Acid A mixture of 10 g. of S-fluoroquinolinic acid dispersed in 100 ml. of nitrobenzene was refluxed until the evolution of carbon dioxide ceased. The mixture was cooled and was extracted with three 50 ml. portions of 5 percent sodium hydroxide solution. The extracts were combined, were extracted with ether to remove traces of nitrobenzene, and were adjusted to about pH 2.5 with dilute hydrochloric acid. The adjusted mixture was cooled to about 0 C. for a few hours, and the S-fluoronicotinic acid which separated was recovered by filtration.

We claim:

1. The method of preparing S-fluoronicotinic acid which comprises oxidizing 3-fiuoroquinoline with nascent oxygen to produce S-fiuoroquinolinic acid and heating the 5-fiuoroquinolinic acid to about ISO-220 C. to decarboxylate said quinolinic acid to 5-fluoronicotinic acid.

2. The method according to claim 1 in which the nascent oxygen is provided by a combination of hydrogen peroxide and a copper salt in an acetic acid solvent.

3. The method according to claim 1 wherein the nascent oxygen is anodic oxygen.

References Cited in the file of this patent UNITED STATES PATENTS 2,371,691 Hawkinson et a1. Mar. 20, 1945 2,389,065 Lee et al. Nov. 13, 1945 2,516,830 Roe July 25, 1950 FOREIGN PATENTS 851,801 Germany Oct. 9, 1952 OTHER REFERENCES Ugai et al.: Chem. Abstracts, vol. 29, p. 3340 (1935) (abstract from J. Pharm. Soc., Japan, vol. 55, pp. 1314 

1. THE METHOD OF PREPARING 5-FLUORONICOTINIC ACID WHICH COMPRISES OXIDIZING 3-FLUOROQUINOLINE WITH NASCENT OXYGEN TO PRODUCE 5-FLUOROQUINOLINIC ACID AND HEATING THE 5-FLUOROQUINOLINIC ACID TO ABOUT 150-220*C. TO DECARBOXYLATE SAID QUINOLINIC ACID TO 5-FLUORONICOTINIC ACID. 